Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral

[fds66]

Just found this abstract - don't have access to the full version. Don't know if someone else has posted it. The title has been cut off in the thread title but I can't edit it. It may be that a mod would like to alter it to make more sense.

http://www.pnas.org/content/early/2010/02/24/0913650107.short?rss=1

Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors

• Harriet C. T. Grooma,
• Melvyn W. Yapa,
• Rui Pedro Galob,
• Stuart J. D. Neilb, and
• Kate N. Bishopa,1

+ Author Affiliations

• aDivision of Virology, MRC National Institute for Medical Research, London NW7 1AA, United Kingdom; and
• bDepartment of Infectious Diseases, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, United Kingdom

• Edited by Stephen P. Goff, Columbia University College of Physicians and Surgeons, New York, NY, and approved February 2, 2010 (received for review November 25, 2009)

Abstract

Xenotropic murine leukemia virus-related virus (XMRV) is a recently discovered gammaretrovirus that has been linked to prostate cancer and chronic fatigue syndrome. This virus is therefore an important potential human pathogen and, as such, it is essential to understand its host cell tropism. Intriguingly, infectious virus has been recovered from patient-derived peripheral blood mononuclear cells. These cells express several antiviral restriction factors that are capable of inhibiting the replication of a wide range of retroviruses, including other gamma retroviruses. This raises the possibility that, similar to HIV, XMRV may have acquired resistance to restriction. We therefore investigated the susceptibility of XMRV to a panel of different restriction factors. We found that both human APOBEC3 and tetherin proteins are able to block XMRV replication. Expression of human TRIM5α, however, had no effect on viral infectivity. There was no evidence that XMRV expressed countermeasures to overcome restriction. In addition, the virus was inhibited by factors from nonhuman species, including mouse Apobec3, tetherin, and Fv1 proteins. These results have important implications for predicting the natural target cells for XMRV replication, for relating infection to viral pathogenicity and pathology, and for the design of model systems with which to study XMRV-related diseases.

 

[leelaplay]

Intriguingly, infectious virus has been recovered from patient-derived peripheral blood mononuclear cells.

Looks like they had no problem finding xmrv

 

[subtr4ct]

Looks like they had no problem finding xmrv

In the full text, the statement about finding XMRV in patient blood is followed by a citation (their reference number 5) to the Lombardi et al paper. I haven't read the full text, but I don't think they are saying they themselves have found XMRV in patient blood.

 

[subtr4ct]

If XMRV is the CFS boogieman, the real value of this paper is perhaps its implications for therapy? See quote below.

I'm not at all qualified to comment on these things, but might these "restriction factors" also play a role in whether or not XMRV can be found in blood or not, versus tissue. Perhaps in mild-to-moderately disabled CFS patients, the restriction factors do keep XMRV out of PBMCs, but not out of tissue. But in the most debilitated patients (Lombardi cohort), the restriction factors are somehow disabled or overwhelmed, and XMRV is in the blood? Could this be another possible explanation for the divergent results of Lombardi et al and the second UK study (Groom, Kerr, and others)? This is totally unqualified speculation; can any experts here comment?

In summary, we report here that exogenous expression of at least two human restriction factors is able to inhibit XMRV, a virus recently linked to two important human diseases. This finding presents new questions as to which cells the virus replicates in vivo, and how it evades restriction by these factors in PBMCs, particularly in the absence of obvious viral countermeasures. Restriction must also be an important consideration in the design of model systems for XMRV infection. Future work will establish whether this virus really does cause disease in humans, but efforts are already under- way to find antiviral therapies and treatments. Restriction factors can now be added to the arsenal of possible defenses.

 

[ukxmrv]

It's interesting that Kate Bishop was a co-author of that paper as she was a co-author of the recent UK failed validation attempt

If anyone has access to the full article could you please let me know what her involvement was?

Many thanks for flagging this up

 

[subtr4ct]

It's interesting that Kate Bishop was a co-author of that paper as she was a co-author of the recent UK failed validation attempt

If anyone has access to the full article could you please let me know what her involvement was?

Author contributions: H.C.T.G., M.W.Y., R.P.G., S.J.D.N., and K.N.B. designed research;
H.C.T.G., M.W.Y., R.P.G., S.J.D.N., and K.N.B. performed research; H.C.T.G., M.W.Y.,
R.P.G., S.J.D.N., and K.N.B. analyzed data; and S.J.D.N. and K.N.B. wrote the paper.

Involved in every aspect, it appears.

 

[Gerwyn]

Involved in every aspect, it appears.

We have ancient innate defences against retroviruses called the intrinsic system.
Part of this system comprises cellular proteins which recognise the protein signature of the virus and stop the coat opening properly.

This means that t cant replicate and is wide open to other enzymes in the cell that break it down.

There a number of these proteins Trim5alpha,tetherin APOBEC3 and TRIM22.

Trim5alpha evolved about 4 million years ago,A particular sequence of amino acids in Trim5 determine whether it can "recognise" a particular retrovirus.

This protein makes a cell more susceptible to HIV infection by a mechanism I dont understand.This how HIV" sneaks in" because this "sentry"doesn,t recognise it and cant call "reinforcements".It looks as if XMRV sneaks in the same way

 

[natasa778]

Part of this system comprises cellular proteins which recognise the protein signature of the virus and stop the coat opening properly.

Where does IFNgamma/Rnase L come in? or is that focused on stopping assembly?

 

[leelaplay]

In the full text, the statement about finding XMRV in patient blood is followed by a citation (their reference number 5) to the Lombardi et al paper. I haven't read the full text, but I don't think they are saying they themselves have found XMRV in patient blood.

Hi subtr4act

If you have access to the full text and if it's ok to, it'd be great if you could post it to the library. If not, thanks for filling in some of the info from the full text.

 

[subtr4ct]

Hi subtr4act

If you have access to the full text and if it's ok to, it'd be great if you could post it to the library. If not, thanks for filling in some of the info from the full text.

I assume sharing the full text for research purposes constitutes fair use. I'm not familiar with the library, though. How can I post it?

 

[leelaplay]

Ah - I'm not sure how all these things really work either. I just noticed that you're new - welcome!

I think that the library had to be set up for senior members (100 posts maybe) as copyright would not be violated by doing it that way. Which means that you can't probably see it or post to it. You could send an email to one of the administrators in the nuts and bolts section asking for help and/or access.

So I'm not really sure how copyright works on posting full articles here. It seems that some publishers allow you to copy full texts. .........And I'm pretty sure that one can copy excerpts that one will discuss. Not sure bottom line.

So sorry I can't be of more help on this issue. Please do whatever you think to be right. You probably know more than I do.

 

[Gerwyn]

Where does IFNgamma/Rnase L come in? or is that focused on stopping assembly?

Ifn gamma has a role in stimulating macrophagess and has direct antiviral activity by stimulating protein kinases which in turn stimulate Rnase L

 

[Jimk]

New Study: Cellular restriction factors and XMRV

Good virology coming out of UK. The fundamental science seems to be doing better than the CFS studies.

Proc Natl Acad Sci U S A. 2010 Mar 1. [Epub ahead of print]
Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors.

Groom HC, Yap MW, Galo RP, Neil SJ, Bishop KN.

Division of Virology, MRC National Institute for Medical Research, London NW7 1AA, United Kingdom.
http://tinyurl.com/yf42qdw

 

[flybro]

WoW great find Jim.

Xenotropic murine leukemia virus-related virus (XMRV) is a recently discovered
gammaretrovirus that has been linked to prostate cancer and chronic fatigue
syndrome.

This virus is therefore an important potential human pathogen and, as
such, it is essential to understand its host cell tropism. Intriguingly,
infectious virus has been recovered from patient-derived peripheral blood
mononuclear cells.

These cells express several antiviral restriction factors that
are capable of inhibiting the replication of a wide range of retroviruses,
including other gamma retroviruses.

This raises the possibility that, similar to HIV, XMRV may have acquired resistance to restriction. We therefore investigated
the susceptibility of XMRV to a panel of different restriction factors. We found
that both human APOBEC3 and tetherin proteins are able to block XMRV replication.

Expression of human TRIM5alpha, however, had no effect on viral infectivity.
There was no evidence that XMRV expressed countermeasures to overcome
restriction. In addition, the virus was inhibited by factors from nonhuman
species, including mouse Apobec3, tetherin, and Fv1 proteins.

These results have important implications for predicting the natural target cells for XMRV
replication, for relating infection to viral pathogenicity and pathology, and for
the design of model systems with which to study XMRV-related diseases.

So do we know anything about

human APOBEC3 and tetherin proteins

or nonhuman species, including mouse Apobec3, tetherin, and Fv1 proteins.

 

[Abraxas]

Thanks Jim, interesting. So this study has two of the same authors as the UK XMRV study #2, Groom HC and Bishop KN.

 

[flybro]

Thanks Jim, interesting. So this study has two of the same authors as the UK XMRV study #2, Groom HC and Bishop KN.

Makes you wonder even more about the cohort issue.

So far studies on XMRV away from CFS are turning up links that fit CFS, ie the recent animal studies.

Irrelevant of CFS the XMRV studies will continue, and eventually the cohort question will cease to exist, as Wessley/Governemts will not be able to control the non-cfs studies.

Looking forward to hearing more about

human APOBEC3 and tetherin proteins

or nonhuman species, including mouse Apobec3, tetherin, and Fv1 proteins.

I hope the Pheonix Big Guns come and disect this and expleain what implications this info has if any on us.

 

[fds66]

Some comments already posted on this other thread about this paper

http://forums.aboutmecfs.org/showth...emia-virus-related-virus-(XMRV)-to-retroviral

 

[Abraxas]

Thanks fds66, hadn't noticed you'd already started a thread on this study

 

[Bob]

"We found that both human APOBEC3 and tetherin proteins are able to block XMRV replication."

So it looks like humans have an existing defense mechanism against XMRV...
and maybe this existing defense mechanism is the reason that XMRV doesn't kill us quickly? (I'm assuming that XMRV causes ME for the sake of discussion)
Maybe this also highlights a genetic disposition to XMRV, in that the pathways which regulate APOBEC3 and tetherin proteins may not be very efficient in people with ME, due to genetic differences?
(just some of my thoughts - but there's not much info here to go on)

 

[Gerwyn]

Makes you wonder even more about the cohort issue.

So far studies on XMRV away from CFS are turning up links that fit CFS, ie the recent animal studies.

Irrelevant of CFS the XMRV studies will continue, and eventually the cohort question will cease to exist, as Wessley/Governemts will not be able to control the non-cfs studies.

Looking forward to hearing more about

human APOBEC3 and tetherin proteins

or nonhuman species, including mouse Apobec3, tetherin, and Fv1 proteins.

I hope the Pheonix Big Guns come and disect this and expleain what implications this info has if any on us.

It means that if it gets past trim alpha it can sneak in like AIDS Can anyone get a copy of the methodology please!!!?